Sodium Hydroxide → 5-Nitroindole-2-carboxylic acid

Participants

Reaction Steps

To a stirred solution of ethyl 5-nitroindole-2-carboxylate (8) (4.3 g, 19.5 mmol) in 100 mL THF-methanol (1:1, v/v), at room temperature under argon, was added a solution of NaOH (12 g, 300 mmol) in 300 mL water. The resulting deep red-brown solution was stirred for 3 h, then quenched by acidification to pH 1 with dilute HCl. Precipitated product was collected by vacuum filtration and the remaining dissolved product was extracted with THF:ethyl acetate (1:1 v/v). The precipitate was dissolved in THF and this solution was combined with the organic layers from the extractions. Drying over magnesium sulfate, and evaporation of the solvent afforded 5-nitroindole-2-carboxylic acid (3.6 g, 90% yield) as a light brown solid: NMR (acetone d6) δ7.0-9.0 (m,4H), δ9.5 (s, 1H), δ12.5 (s, 1H). To a stirred solution of 5-nitroindole-2-carboxylic acid (3.1 g, 15 mmol) in 150 mL THF, under argon, was added oxalyl chloride (4.8 g, 37.6 mmol) followed by 0.1 mL of DMF which caused a vigorous evolution of gas. After 40 min, the reaction mixture was evaporated to dryness. The resulting solid was redissolved in 100 mL THF and cooled to -23° C. and stirred under argon. A solution of potassium t-butoxide (1.0M in THF, 45 mL, 45 mmol) was then added dropwise over 30 min, and stirring was continued for an additional 20 min. The reaction was quenched with 5 volumes of water, neutralized with dilute HCl, and extracted with ethyl acetate. The organic extracts were washed with saturated aqueous sodium bicarbonate and water, then dried over magnesium sulfate, filtered, and concentrated to afford 6 (3.24 g, 83% yield) as a brown solid:NMR (acetone-d6) δ1.6 (s, 9H), δ7.4-8.9 (m, 5H).

Provenance & Evidence